E. Sercarz, P. van den Elzen, V. Kumar, J. Beech and E. Maverakis

Among the self-reactive T cell clones that respond to the acetylated amino terminal nonamer of myelin basic protein (Ac1-9 of MBP), only one clone manifests itself as a driver of the disease, experimental autoimmune encephalomyelitis (EAE). This clone uses a Vb8.2, Jb2.7 TcR which has a 9-amino acid long CDR3 which features the residues DAGGGY, and was found in the spinal cord during the onset of disease, as detected by the "immunoscope" technology of Kourilsky and his colleagues. This clone has a high affinity for antigen, and is Th1 in character. Thus, only a minority of the self-reactive repertoire is pathogenic, and this portion is found in each mouse. It was then possible to follow the fate of this critical repertoire component via the immunoscope, to learn that the driver clone is deleted from any lymphoid organ in the individual, while many non-pathogenic Th2 cells can still be found. From earlier work, we know that the Vb8.2 driver clone is removed by a regulatory pair of CD4 and CD8 T cells and that the residual population is Th2 in nature. Accordingly, what appears to be a deviation at the single cell level is actually occurring at the global level, since a different repertoire remains with different T cell receptors.

A striking aspect of these experiments as well as others in the NOD system,is that such a few T cells dominate the pathogenic response. Driver clones appear to be unusual in several ways and occupy a special role in the induction of regulation. They probably all have high affinity for Ag, produce large quantities of cytokines, are especially sensitive to costimulation and to regulation, etc, a group of characteristics that remain to be established for such T cell clones. These clones no doubt establish their hegemony by getting a better head start in the response to antigen.

We believe that these results call for some reevaluation of some problems in autoimmunity. For example, it would appear sufficient to target driver clones to control autoimmune pathogenesis and determinant spreading.

Figure 1 (PDF):
The VbJb usage of cells responding to Ac1-9 is diverse and involves many private members and one public member. The distribution of T cell expansions within the Vb8.2 and Vb13 repertoires for all 12 Jbs (Jb1.1à Jb2.7 = Jb1.1, Jb1.2, Jb1.3, Jb1.4, Jb1.5, Jb1.6, Jb2.1, Jb2.2, Jb2.3, Jb2.4, Jb2.5, Jb2.7). Those with a relative index of stimulation (RIS) of 2-4 are depicted by a striped box, and those with an RIS of 4 or more with a black box. Several expansions specific for Ac1-9 are seen in each animal at the onset (A) and during recovery (B) of EAE. The dominant, public expansion is Vb8.2Jb2.7 with a CDR3 length of 9 amino acids. All other expansions are deemed private. Upon recovery, the public clone is lost, while the private repertoire remains. With the exception of the public clone, CDR3 lengths of private expansions usually differed from others in the same VbJb pair. EAEy denotes the anatomical location (y), s=spleen and c=spinal cord. C) The 9 amino acid expansion within the splenic Vb8.2Jb2.7 set arises specifically from Ac1-9 restimulation (3 days in vitro with 40 ug/mL Ac1-9), but not from various controls represented by the shaded spectra (naïve, irrelevant antigen or CFA immunized). The average relative index of stimulation (RIS) was 8.8. Importantly, the subset infiltrating the spinal cord reveals this expansion directly ex vivo (bottom panel), without the need for in vitro restimulation. D) Mice were analyzed identically between days 25-30 post-immunization, and although the Vb8.2Jb2.7 expansion occasionally occurred, it was no longer public, and the average RIS was only 1.5. Six of the seven mice no longer revealed the expansion in the spinal cord, and many fewer cells were recoverable.